PROJECT SUMMARY/ABSTRACT Uterine fibroids (UL, uterine leiomyomas) are benign smooth muscle cell (SMC) tumors of the myometrium. Leiomyomas represent the most frequent clinical indication for hysterectomy that often prematurely ends a woman's fertility. In the year 2010, the estimated annual cost of uterine fibroid tumors in the United States was up to $34.4 billion. Yet in spite of this, there are currently no approved drugs that can provide effective, long-term treatment for UL. There is an unmet need to identify molecular targets and to develop therapies to treat uterine fibroids. The goal of our research is to understand the molecular pathogenesis of uterine UL so that effective pharmacotherapies could be developed. Dysregulated PI3K/AKT pathway leading to the activation of mTOR play an essential role in the pathogenesis of leiomyomas. Our preliminary data suggest that GPR10, a GPCR normally silenced in the periphery by the tumor suppressor REST/ NRSF, is near ubiquitously over-expressed human leiomyomas, which harbor a very high degree of heterogeneity in other markers. Further, REST protein is dramatically reduced in leiomyomas. Crucial to the current project, the activation of GPR10, or the loss of REST triggers PI3K/AKT signaling and tumor cell proliferation. We hypothesize that the loss of REST leads to GPR10 expression in leiomyomas and this aberrant gene expression functionally promotes cell proliferation contributing to the pathogenesis of uterine fibroids. The current project will establish the functional role that REST-GPR10-AKT-mTOR pathway has on the pathogenesis of uterine fibroids using in vitro methods and novel in vivo genetic models. Additionally, the project will identify, conduct structure activity relationship (SAR) studies, and pre-clinically test, small molecule GPR10 antagonists as potential treatments for UL.